The following description of the background is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention.
Prodrugs are frequently used to improve certain properties of pharmacological agents for a preferred route of administration, including physicochemical, biopharmaceutical or pharmacokinetic properties. Certain prodrugs (also called soft drugs) are designed by tissue selective activation or deactivation to achieve therapeutic advantages (See J. Rautio, et al. Nature Reviews Drug Discovery 7: 255-270 (2008)).
Certain cyclic phosphate, phosphonate, phosphonamidate, and phosphoramidate prodrugs are disclosed in U.S. Pat. Nos. 6,312,662 and 7,205,404 and designed for liver-targeting of pharmacological agents. These prodrugs are activated by liver cytochrome P450 enzymes CYP3As that are predominantly expressed in the target tissue and designed to achieve the selective delivery of pharmacological agents to the liver. Since the prodrugs are not active outside the liver, the liver-targeting strategy reduces pharmacological or toxicological effects of a biologically active agent outside the targeting tissue. As a result, once used to treat liver diseases or to treat diseases via intervening in molecular pathways in the liver, the liver-targeting significantly improves patient benefit/risk ratio of a pharmacological agent (e.g. see M. D. Erion, et al. J Pharm Exp Ther 312:554-60 (2005)).